Latest HIV 'cure' claims prompt calls for more caution

HIV has been undetectable for more than three years in the blood of two Australian bone-marrow recipients. But recent relapses of other patients who had no detectable virus have dampened optimism about how long the effects last before the virus bounces back.

“Results of relapses in other patients should serve to warn us about the use of the phrase ‘viral clearance’,” says Asier Sáez-Cirión of the Pasteur Institute in Paris. “We need to be careful about assumptions made when patients are still on antiretroviral drugs,” he says.

The latest results from Australia, presented on Saturday in Melbourne, Australia, at the international AIDS 2014 conference, add to evidence that bone marrow transplants seem to have a strong but as yet unexplained antiviral effect in patients with HIV. However, the impact of the transplants is difficult to interpret because the patients have also remained on antiretroviral drug therapy (ART), making it difficult to disentangle the effects of bone marrow transplant and ART on viral levels.

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The results also add to a growing catalogue of cases in which the virus is driven to such low levels that the outcome almost equates to a cure, either through bone marrow transplants or through early treatment of patients with ART before the virus can establish itself and hide away in the body (see timeline).

Growing cure club

“In our two patients, we can’t detect HIV,” said David Cooper of the University of New South Wales’s Kirby Institute in Sydney, Australia, and presenter of the results from the patients who received transplants at St Vincent’s Hospital in Sydney. “Nor can we find antibodies to the virus, as they all seem to have disappeared from our patients’ serum,” he said.

The results mean that in total, five people worldwide have now cleared detectable virus from their blood following bone marrow transplants. As in the previous cases, the two patients in Sydney received their transplants to treat blood cancers, but they also happened to be chronically infected with HIV&colon; one since 2003 and one since 1987.

Only one of the five people has been completely cured of HIV. Timothy Ray Brown, also known as the “Berlin patient“, owes his remission to the fact that he received a bone marrow transplant from a donor who was fully resistant to HIV.

HIV resistance is provided by a variant of a gene called CCR5. The normal version of the gene makes a protein on the surface of white blood cells that HIV uses as a “door handle” to invade and kill the cell. Donors who are fully resistant have two “faulty” versions of the gene, which produce a misshapen protein that the virus cannot latch onto.

HIV strikes back

Two further patients, known as the “Boston patients“, received bone marrow from normal donors, but each patient naturally had single copies of a faulty version of CCR5, giving them partial resistance to the virus. However, both Boston patients relapsed late last year after appearing to have been cured last July, and had to resume drug treatments.

Neither of the Sydney patients had any natural resistance. One received a graft from a resistant donor who had one faulty copy of the CCR5 gene. But the other patient’s bone marrow came from a donor who made normal versions of the gene, and yet the transplant recipient was still apparently able to suppress the virus.

“The bone marrow in this patient didn’t contain any protective genes,” says Cooper. “This is a very important clue, that an immune response prompted by the bone marrow transplant has such a strong anti-HIV effect,” he says.

By experimenting on samples from the patients, Cooper hopes to work out how this happens. “Maybe we can find therapies that mimic what we’re doing with the bone marrow transplant, but without having to do actual transplants,” he says.

Both patients have remained on ART. “We need to study more of these patients to understand what the anti-HIV effect is, where the virus is hiding and when it would be safe to stop ART,” says Cooper. He suspects that if the ART was stopped, the virus would come back.

Likewise, relapses have recently been reported in high-profile patients who appeared to have the virus under control through treatment early after infection. The best-known case, the “Mississippi baby“, was reported last year. The child went without ART for four years and showed no sign of HIV infection, but resumed ART last month following the discovery that the virus had rebounded.

In light of the relapses, Sharon Lewin of Monash University in Melbourne, Victoria, also sounded a note of caution about the Australian results. “Given what we know with the Boston patients, the real test of whether transplantation has made a difference to the reservoir will be a treatment interruption”, she says.

“All these cases are helpful in better understanding how transplantation can impact the reservoir,” says Lewin. “I know there are several other similar cases around – but they are all still on ART.”

The major barrier to finding a cure is that the virus lays dormant in tissues of the gut, lymph system, bloodstream and elsewhere, but reawakens and begins invading blood cells if patients halt ART. The best hope is using drugs such as vorinostat that completely “flush out” the virus so it can be killed outright with antiretroviral drugs. Trials with these treatments are currently under way in several laboratories around the world.

A timeline of “cures”

The two Australians appear to have been cleared of the virus. But this timeline shows it may be too soon to celebrate the results as cures. HIV has a nasty habit of hiding in the body and returning just when researchers think it’s gone for good.

November 2008 – Berlin patient “cured”A haematologist in Berlin declares that a man with HIV has been “functionally cured” after receiving a bone marrow transplant from a donor with natural immunity to the virus. The transplant was intended to treat the man’s leukaemia, but his doctor chose a donor with a gene mutation that prevents HIV from entering cells. Only one per cent of Europeans have this mutation, so the treatment is unlikely to work on a large scale.

March 2013 – Mississippi baby “cured”A baby born with HIV is said to be “cured” after an intensive treatment programme that was started within 30 hours of her birth. The infant, known as the “Mississippi baby”, was treated with a combination of three antiretroviral drugs for 18 months, after which doctors lost track of her. When she was taken to a clinic ten months later, physicians found her blood remained free of the virus.

March 2013 – Visconti cohort “cured”Within weeks of the announcement of the “cured HIV baby” comes further good news&colon; 14 adults with HIV appear to be functionally cured after receiving therapy for three years. These individuals, known as the Visconti cohort, still have HIV in their blood, but at levels that are low enough for the immune system to control the virus without drugs. None of these adults has the genetic mutation that might make a person naturally resistant to infection – it is the drug therapy that seems to offer long-term protection.

July 2013 – Boston patients “cured”Two men known as the Boston patients appear to have rid their bodies of HIV, although researchers stop short of declaring them cured. Both men had already been diagnosed with HIV and were taking antiretroviral drugs when they received bone marrow transplants to treat Hodgkin’s lymphoma, a form of blood cancer. A few years after receiving their transplants, the men stopped taking their HIV medicine. One man was found to be virus-free 15 weeks after halting his therapy, whereas the other man showed no signs of the virus seven weeks after he stopped taking his medicine.

December 2013 – HIV detected in Boston patientsFive months after the Boston patients were thought to have rid their bodies of active HIV, the virus is found to have returned in both of them. Both men resume taking antiretroviral drugs.

July 2014 – HIV detected in Mississippi babyMore bad news&colon; the “Mississippi baby” thought to have been cured back in 2013 is diagnosed with the virus. The virus was identified in the blood of the girl, now nearly four, during a routine medical appointment.